Tryptophan
and unnatural tryptophan derivatives are important building blocks for the
total synthesis of natural products, as well as the development of new drugs,
biological probes, and chiral small molecule catalysts. As part of our research program
aimed at establishing new methods for the enantioselective synthesis of
alkaloids, we became interested in developing convergent syntheses of
tryptophans and cyclo-tryptophans (also known as pyrroloindolines) from simple
indole starting materials. Our research funded by this Doctoral New
Investigator award from the ACS PRF has resulted in the first direct,
enantioselective synthesis of tryptophan derivatives by a tandem
Friedel–Crafts conjugate addition/asymmetric protonation reaction. These
reactions require no pre-activation of the indole substrates, and provide
convergent access to a range of substituted tryptophan derivatives in enantioenriched
form.

In 2010,
we reported a new reaction for the preparation of enantioenriched pyrroloindolines
(3) in which (R)-BINOL¥SnCl4 catalyzes a
formal (3 + 2) cycloaddition reaction between 1,3-disubstituted indoles (1) and benzyl
2-trifluoroacetamidoacrylate (2a) (Figure 1, a).[1] Good yields, moderate exo:endo diastereoselectivities, and high
enantioselectivities were obtained for a variety of indole substrates.
Unexpectedly, our studies revealed that the initially formed exo- and endo-diastereomers of 3 were generated in opposite
enantiomeric series. These findings led us to propose that pyrroloindoline
formation proceeds by a stepwise mechanism, in which an initial conjugate
addition of indole 1 to 2a is
followed by a highly selective catalyst-controlled protonation to give 5. Subsequent cyclization of the
amide onto the iminium ion provides the pyrroloindoline product (3).

We
hypothesized that a (R)-BINOL¥SnCl4 complex serves as a chiral Lewis acid-assisted
Brznsted acid (LBA)[2],[3] to effect an asymmetric protonation
of the enolate intermediate. Although Yamamoto and coworkers initially
developed (R)-BINOL¥SnCl4
as an LBA to effect enantioselective protonation of silyl enolates, these
complexes had never previously been used in tandem conjugate
addition/asymmetric protonation reactions. We hypothesized that the combination
of (R)-BINOL and
SnCl4 could catalyze the reaction of 2-amido acrylates with C2-substituted
indoles to provide
unnatural tryptophan derivatives. Key to this transformation is a
catalyst-controlled protonation to set the absolute configuration of the key a-amidoester stereogenic center
(Figure 1, b).

To test
this hypothesis, 2-phenylindole (6a) and benzyl 2-trifluoroacetamidoacrylate (2a) were subjected to the reaction
conditions previously optimized for the enantioselective formal (3 + 2)
cycloaddition reaction.Somewhat surprisingly, the desired reaction was sluggish under these
conditions: after 2 hours, trifluoroacetamido ester 7a was formed in low yield and poor
enantiomeric excess (Figure 2). In an effort to improve the reactivity, a
screen of additional 2-amidoacrylates was conducted. Gratifyingly, the use of
commercially available methyl 2-acetamidoacrylate (2b) gave substantially improved
results, providing acetamido ester 7b in 73% yield and 78% ee (not shown). A further survey
of additives and BINOL derivatives revealed that use of 3,3'-dibromo-BINOL as
the catalyst and 4 molecular sieves as an additive provided 7b in 76% yield and 93% ee.

Having
identified conditions to prepare acetamido ester 7b in high yield and enantiomeric
excess, a survey of indole substrates was conducted to evaluate the scope of
the reaction. Substitution of the 2-phenylindole backbone at the 4, 5, 6, and
7-positions is well tolerated (entries 4–7). Whereas substrates bearing
either electron-donating or electron-withdrawing substituents furnish products
with high enantioselectivity, the more electron-poor indoles are less reactive
and provide lower yields of the acetamido ester products even with 1.6 equiv of
SnCl4 (entries 9 and 10). A range of substituents are tolerated at
the 2-position of the indole, including both aryl and alkyl groups.
2-Arylindoles bearing substituents in either the m- or p-position of the arene are
accommodated; on the other hand, o-substituted arenes are substantially less reactive (entries
12 and 16). For indoles containing 2-alkyl substituents, the ee improves in
switching from a methyl group to the slightly larger n-butyl and i-propyl substituents (entries
18-20); however, both the yield and selectivity are diminished in the case of
bulky t-butyl
substitution (7w,
entry 22).

Importantly, this award has provided these students with the
opportunity to conduct exciting research in the area of asymmetric catalysis.
Several members of my group have worked on various aspects of this project, and
it has proven to be a fertile area for both mechanistic studies and synthetic
applications. The support provided by this DNI award has positively impacted my
career by providing me with the opportunity to pursue exciting, fundamental
research in the area of asymmetric catalysis. I expect that the findings described
here will continue to drive an exciting area of research in my laboratory for
many years to come.